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Molecular Basis of the Rapamycin Insensitivity of Target Of Rapamycin Complex 2 |
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Authors | ![]() | |
Published in | Molecular cell. 2015, vol. 58, no. 6, p. 977-988 | |
Abstract | Target of Rapamycin (TOR) plays central roles in the regulation of eukaryote growth as the hub of two essential multiprotein complexes: TORC1, which is rapamycin-sensitive, and the lesser characterized TORC2, which is not. TORC2 is a key regulator of lipid biosynthesis and Akt-mediated survival signaling. In spite of its importance, its structure and the molecular basis of its rapamycin insensitivity are unknown. Using crosslinking-mass spectrometry and electron microscopy, we determined the architecture of TORC2. TORC2 displays a rhomboid shape with pseudo-2-fold symmetry and a prominent central cavity. Our data indicate that the C-terminal part of Avo3, a subunit unique to TORC2, is close to the FKBP12-rapamycin-binding domain of Tor2. Removal of this sequence generated a FKBP12-rapamycin-sensitive TORC2 variant, which provides a powerful tool for deciphering TORC2 function in vivo. Using this variant, we demonstrate a role for TORC2 in G2/M cell-cycle progression. | |
Keywords | Antifungal Agents/metabolism/pharmacology — Binding Sites/genetics — Biocatalysis/drug effects — Blotting — Western — Carrier Proteins/chemistry/genetics/metabolism — Cell Cycle/drug effects/genetics — Cell Cycle Proteins/chemistry/genetics/metabolism — Drug Resistance/genetics — Mass Spectrometry/methods — Mechanistic Target of Rapamycin Complex 2 — Microscopy — Electron — Multiprotein Complexes/chemistry/genetics/metabolism — Mutation — Phosphatidylinositol 3-Kinases/chemistry/genetics/metabolism — Protein Structure — Tertiary — Saccharomyces cerevisiae/drug effects/genetics/metabolism — Saccharomyces cerevisiae Proteins/chemistry/genetics/metabolism/ultrastructure — Sirolimus/metabolism/pharmacology — TOR Serine-Threonine Kinases/chemistry/genetics/metabolism | |
Identifiers | PMID: 26028537 | |
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Structures | ||
Research group | Groupe Loewith | |
Citation (ISO format) | GAUBITZ, Christl et al. Molecular Basis of the Rapamycin Insensitivity of Target Of Rapamycin Complex 2. In: Molecular Cell, 2015, vol. 58, n° 6, p. 977-988. doi: 10.1016/j.molcel.2015.04.031 https://archive-ouverte.unige.ch/unige:103227 |